Robert M. Gill

Ventricular refractory period extension caused by defibrillation shocks.

In pentobarbital-anesthetized dogs, transcardiac shocks of up to 30 J or pacing stimuli were delivered to myocardial tissue at different times in the electrical cycle. When delivered midway or later into electrical systole, shocks, but not pacing stimuli, greatly extended the refractory period as determined by left ventricular pacing. There was a positive correlation between both the shock energy and timing and the amount of delay. A 30-J shock given 10 msec before the end of the refractory period extended the refractory period by 63 +/- 15 msec (p less than 0.001), whereas the same shock given 40 msec earlier produced only 25 +/- 10 msec (p less than 0.001) of extension. By comparison, a 5-J shock given at those times produced 36 +/- 18 (p less than 0.005) and 10 +/- 8 msec (p less than 0.001) of extension, respectively. When delivered early into electrical systole, both a pacing stimulus and a shock had no substantial effect on the tissue refractory period. Because the tissue that is late in electrical systole would otherwise be the first to repolarize if no shock were given, the selective refractory period extension may create a period after the shock during which no tissue is repolarized to a level sufficient for wavefront propagation. Thus, the energy- and time-dependent refractory period extension may help explain the mechanism by which ventricular defibrillation occurs during transcardiac shocks.

Characterization of refractory period extension by transcardiac shock.

BackgroundTo better understand the refractory period extension (RPE) produced by transcardiac shocks and its possible role in defibrillation, we measured RPE under various experimental conditions. Methods and ResultsUsing ventricular pacing in pentobarbital-anesthetized dogs, we characterized RPE in relation to the anatomic site of pacing, the local voltage gradient (LVG) produced by the shocks at the pacing site, and the pacing rate and pacing current used to make the measurements. We also determined ifRPE persisted into the next refractory period after the shock and measured RPE at the end of 30-second episodes of acute ischemia to the pacing site, which were caused by occluding the left anterior descending artery. Each anatomic site tested showed RPE, which increased sharply with increasing LVG at lower levels but less sharply at higher LVG. The RPE versus LVG was approximated with an exponential curve that had an exponential constant of about 5-6 V/cm. At faster pacing rates, RPE occurred earlier in the refractory period but was unchanged when expressed as a percent increase of refractory period. RPE did not vary with the pacing current and was present only in the refractory period during which the shock was delivered. The RPE was not significantly altered by acute ischemia. These results show that transcardiac shocks selectively extend the refractory period of tissue proportional to the LVG and the timing of the shock in the refractory period. They are consistent with the concept that RPE prevents depolarization from tissue directly excited by a shock from propagating to tissue that was refractory to that same shock. ConclusionsThe insensitivity of RPE to short ischemic episodes and the presence of RPE at increased activation rates suggest that RPE might exist under conditions of fibrillation and be a major determinant of the success or failure of defibrillation. (Circulation 1991;83:2057—2066)

The defibrillation threshold: a comparison of anesthetics and measurement methods.

In 18 open‐chested mongrel dogs (18.0 ± 1.7 kg) we compared three anesthetics and three methods for measuring the defibrillation threshold. Six animals were anesthetized with pentobarbital (30 mg/kg) and maintained with a pentobarbital infusion (4 mg/kg per hour). All other animals were anesthetized with sodium brevital (10 mg/kg) and maintained with either halothane gas (1.5%, N = 6) or isoflurane gas (1.8%, N = 6). In each dog. we measured the energy required for 50% successful defibrillation (E50) with: (A) a 3 reversal—up/down method; (B) a 15 shock—up/down method; and (C) a percent success method. Anesthetics and methods were selected in a balanced random order. Ventricular fibrillation was induced with 50 Hz electrical pacing. After 15 seconds, monophasic truncated exponential shocks were delivered by way of a spring‐patch electrode configuration. The animal was rescued (if needed) and fibrillation/defibrillation episodes were repeated at 3 minute intervals. After each determination of the E50, the E50 was delivered in ten successive defibrillation trials to determine its actual success rate. We found no significant difference in E50 among anesthetics; a significant difference (P < 0.05) in E50 between method C (9.7 ± 2.6 joules) and method B (8.2 ± 1.6 joules); no significant difference among anesthetics or methods for the actual success rate of the E50 (45 ± 21% successful); and method A required significantly fewer fibrillation episodes and number of shocks and less cumulative energy than the other methods. We concluded that the anesthetics tested had little effect on E50 but that the method used to determine E50 could have an effect. Also, the E50 estimated by all methods consistently produced an actual success rate lower than 50%.

High-Resolution Quantitative Computed Tomography Demonstrating Selective Enhancement of Medium-Size Collaterals by Placental Growth Factor-1 in the Mouse Ischemic Hindlimb

Background— The process of arteriogenesis after occlusion of a major artery is poorly understood. We have used high-resolution microcomputed tomography (&mgr;-CT) imaging to define the arteriogenic response in the mouse model of hindlimb ischemia and to examine the effect of placental growth factor-1 (PlGF-1) on this process. Methods and Results— After common femoral artery ligation, &mgr;-CT imaging demonstrated formation of collateral vessels originating near the ligation site in the upper limb and connecting to the ischemic calf muscle region. Three-dimensional &mgr;-CT and quantitative image analysis revealed changes in the number of segments and the segmental volume of vessels, ranging from 8 to 160 &mgr;m in diameter. The medium-size vessels (48 to 160 &mgr;m) comprising 85% of the vascular volume were the major contributor (188%) to the change in vascular volume in response to ischemia. Intramuscular injections of Ad-PlGF-1 significantly increased Sca1+ cells in the circulation, α-actin–stained vessels, and perfusion of the ischemic hindlimb. These effects were predominantly associated with an increase in vascular volume contributed by the medium-size (96 to 144 &mgr;m) vessels as determined by &mgr;-CT. Conclusions— High-resolution &mgr;-CT delineated the formation of medium-size collaterals representing a major vascular change that contributed to the restoration of vascular volume after ischemia. This effect is selectively potentiated by PlGF-1. Such selective enhancement of arteriogenesis by therapeutically administered PlGF-1 demonstrates a desirable biological activity for promoting the growth of functionally relevant vasculature.

Refractory Interval After Transcardiac Shocks During Ventricular Fibrillation

BACKGROUND Measurements of refractory period extension by shocks during ventricular pacing at fast rates predict that all tissue should be refractory for a brief interval after shocks during fibrillation. This study experimentally determined whether a refractory interval was present just after a shock during fibrillation. METHODS AND RESULTS In pentobarbital-anesthetized dogs, rectangular monophasic (4-ms) or biphasic (2.5/1.5-ms) shocks were followed with a 2-ms postshock stimulus (PSS) delivered to the defibrillation electrodes. We measured the effect of PSS on the shock current (I50) required for 50% defibrillation success. In group 1 (n = 6), a 1.0-A PSS had no effect on I50 when delivered up to 35 ms after monophasic shocks but greatly increased I50 when delivered at 50 to 90 ms. A 0.5-A PSS had no effect at any timing. In group 2 (n = 6), we compared 1.0-A PSSs after monophasic and biphasic shocks. The effect of PSS after monophasic shocks was similar to group 1. After biphasic shocks, PSS at the same timings had similar effects but caused even greater increases in I50. CONCLUSIONS We conclude that after both monophasic and biphasic shocks during fibrillation, there is a postshock interval during which the heart is refractory to the refibrillating effect of PSS. The interval is shorter for biphasic than for monophasic shocks with the same duration and defibrillation efficacy. These findings support the refractory period extension hypothesis for defibrillation and suggest that propagating depolarization activity is absent immediately after defibrillation shocks but that it develops again at the end of the refractory interval or later.

Refractory period extension during ventricular pacing at fibrillatory pacing rates.

Refractory period extension (RPE) bas been proposed as a basic mechanism for defibrillation but it remains unclear if RPE exists at the fast rates associated with ventricular fibrillation. In 7 pentobarbital anesthetized dogs, we measured refractory periods with and without 8 ms rectangular transcardiac shocks at left ventricular pacing rates of 200–600 beats/min. To achieve these high rates, an incremental rate pacing method was used to produce pacing train timing sequences requiring 4.5–27 seconds. A variably timed premature stimulus followed the last stimulus in each pacing train. To determine refractoriness, a 128 electrode arrav (4 × 4 cm) was used to detect the presence, or absence of an activation sequence sweeping away from the pacing site. At each rate, a control refractory period (RPc) was measured and refractory periods were also measured for 8 and 12 V/cm shocks with coupling intervals of 60% to 90% of RPc. RPc decreased as the rate increased with a minimum RPc of 94 ms at a rate of 600 beats/min (100 ms cycle length). RPE/RPc versus shock coupling interval was similar at all pacing rates. RPE/RPc increased with increased coupling interval or higher shock intensity. We conclude that during ventricular pacing at fibrillatory rates tissue is nearly always in a refractory state: that RPE exists at fibrillatory activation rates; and that RPE/RPc versus shock coupling interval does not vary strongly with pacing rate. These findings support the hypothesis that RPE contributes to defibrillation.

Selective activation of PI3Kα/Akt/GSK-3β signalling and cardiac compensatory hypertrophy during recovery from heart failure

Activation of phosphoinositide‐3 kinase (PI3K) is essential for cell growth, relating to adaptive and maladaptive cardiac hypertrophy. This longitudinal canine study was designed to investigate the role of PI3Kα and PI3Kγ in cardiac remodelling during congestive heart failure (CHF) and cardiac recovery (CR).

Double-pulse defibrillation using pulse separation based on the fibrillation cycle length.

Double‐Pulse Defibrillation Using FCL, Introduction: We investigated a method of defibrillation in which two shocks were delivered to the same electrodes with a separation hazed on the cycle length of the fibrillation event (FCL).

Effects of Flecainide, Encainide, and Clofilium on Ventricular Refractory Period Extension by Transcardiac Shocks

Objective: The mechanisms by which pharmacological agents alter electrical defibrillation are not fully understood. It has been proposed that, in addition to directly stimulating tissue, defibrillation may involve refractory period extension (RPE) produced by the shock. Accordingly, pharmacological agents might modulate defibrillation by altering RPE. This study examined the effect of Class I and Class III antiarrhythmic agents on RPE by transcardiac shocks. Methods: In four groups of pentobarbital anesthetized dogs, RPE was measured during rapid ventricular pacing before and after administration of either the Class I agents flecainide (n = 7) or encainide (n = 7), the Class III agent clofilium (n = 7), or vehicle (n = 5). Measurements included QRS duration during sinus rhythm and a conduction time, QTC interval and refractory period, and RPE for 4‐ to 10‐V/cm shocks delivered 20–80 ms before the end of the tissue absolute refractory period. For the 6‐V/cm shocks, the interval after the shock during which tissue remained refractory (RIAS) was also computed. Results: Drugs affected QRS duration, conduction time, QTC, and refractory period (without shocks) in accordance with their anticipated Class I and Class III actions. Without drugs, significant RPE was observed in all animals for all shocks delivered 40 ms or less before the end of the refractory period. Clofilium, encainide, and flecainide had a tendency to increase RPE hut only clofilium produced a significant increase. For 6‐V/cm shocks with different timings, the minimum RIAS was found to be approximately 43 ms, and occurred for shocks given 20–30 ms before the end of the refractory period. Conclusions: At drug dosages that produced moderate Class III (=15%) or strong Class I (=35%) effects, only the Class III agent significantly increased RPE and RIAS. Thus, in addition to altering tissue excitability, the effect of antiarrhythmic agents to increase RPE and the minimum RIAS may help explain their influence on defibrillation threshold.

Characteristics of Multiple‐Shock Defibrillation

Multiple‐Shock Defibrillation. Introduction: A new method for defibrillation allows two shocks to be combined to defibrillate with reduced current by adjusting their separation according to the cycle length of the fibrillation event. We investigated various aspects of this new method to better understand its characteristics and applicability to defibrillation.